Drug delivery graft

ABSTRACT

An improved drug delivery graft comprises a drug delivery device coupled to an outer wall of a porous graft. An agent is conducted by the drug delivery device from a source to the outer wall of the graft where it is released to diffuse into the lumen of the graft through porous interstices of the outer wall.

FIELD OF THE INVENTION

[0001] The present invention relates to medical devices, and moreparticularly, to a graft for delivering an agent into a natural tissueconduit, e.g., a blood vessel.

BACKGROUND OF THE INVENTION

[0002] Providing frequent, direct delivery of bioactive agents to anatural tissue conduit has become a necessity for many medicaltreatments such as those requiring frequent intravenous administrationof drugs. To meet this need, many types of devices including stents andvascular grafts have been used to deliver agents into natural tissueconduits.

[0003] Local delivery is advantageous in that the effective localconcentration of a delivered drug can be much higher than can normallybe achieved by systemic administration. Delivery of agents to vasculartissue to prevent restenosis is especially useful. U.S. Pat. No.5,399,352 to Hanson discloses a device for delivering an effectiveconcentration of a therapeutic agent locally at a target site within thebody without producing unwanted systemic side effects. However, thedevice described in this reference differs considerably from existingvascular grafts. It would be especially advantageous to deliver drugswith a device more similar to currently used vascular grafts.

[0004] Stents and other existing devices are frequently coated with orimpregnated with therapeutic agents for the treatment of diseases. Aconcern related to the use of stents and existing devices for drugdelivery is that drug delivery may not be sustainable. Over time theconcentration of drug on the stent or other similar delivery deviceswill diminish, through drug inactivation, degradation, or dilution.Thus, the therapeutic agent may need to be refreshed or even changedafter implant of the device. Moreover, these existing devices are notcapable of delivering drugs to an internal lumen along the entire lengthof the graft.

[0005] Accordingly, it would be desirable to provide a drug deliverygraft capable of delivering a drug or any other agent to the internallumen along the entire length of the graft, or restrict delivery to afinite area on the graft such that the agent may be renewed or alteredafter implant of the graft. Furthermore, a desirable drug delivery graftcould be implanted in the same fashion as regular vascular grafts.

BRIEF SUMMARY OF THE INVENTION

[0006] In accordance with the teachings of the present invention, animproved drug delivery graft is provided. The invention can be used, forexample, as a vascular graft providing sustained release of a selectedbioactive or diagnostic agent directly into a blood or other fluid flowpathway. The graft is capable of delivering the bioactive or diagnosticagent to the internal lumen of a vascular graft along the entire length,or of restricting delivery to a finite area of the vascular graft. Thegraft is preferably made of expanded polytetrafluoroethylene (ePTFE),but could certainly be made of any other porous type graft. VariousePTFE grafts that are reinforced by external beading are well known inthe art. However, unlike previous designs that utilize a solid beadingfor reinforcing purposes, one embodiment of the present inventionutilizes a hollow tubing as a drug conduit. The hollow tubing behavesmuch like the existing low profile solid beading in that it has a smalldiameter and can be readily implanted into the body, offering advantagesas both a spiral support and drug conduit.

[0007] In a preferred embodiment of the present invention, a simpletubular ePTFE graft is used, which is well known to be extremely porous.A hollow tubing of non-porous PTFE, fluoroethylene polymer (FEP) orother implantable polymer is wrapped around the graft and laminated oradhered in place. The hollow tubing may be wrapped helically;alternatively other arrangements (e.g., end to end loops) can be used.Before the wrapping occurs, one surface of the hollow tubing is cut away(for example, laser cut), punctured repeatedly or otherwise renderedporous. When an agent such as a drug is injected into the hollow tubing,e.g., from an infusion pump or a subcutaneous access port, the drugflows through the hollow tubing and leaks through the cut or porousregion and diffuses into the outer surface of the ePTFE graft. The drugdiffuses into the graft where it mixes into the blood flowingtherethrough and influences biological processes along the circulatorysystem. Depending on the drug used and the precise configuration of thedevice the dispensed material could have either systemic effect or havelimited local effect. One particularly attractive use of the device isto dispense drugs to limit the restenosis that frequently occurs due totissue proliferation at the site of anastimosis of an ePTFE graft to ablood vessel.

[0008] The invention takes advantage of the well-known porosity of anePTFE graft. Impregnation of ePTFE grafts with therapeutic agents hasbeen previously disclosed. However, the present invention allows thetherapeutic agents to be renewed or altered following implant of thegraft, something that is not possible with simple drug-impregnated graftmaterials.

[0009] A more complete understanding of the ePTFE drug delivery graftwill be afforded to those skilled in the art, as well as a realizationof additional advantages and objects thereof, by a consideration of thefollowing detailed description of the preferred embodiment. Referencewill be made to the appended sheets of drawings that will first bedescribed briefly.

BRIEF DESCRIPTION OF THE DRAWINGS

[0010]FIG. 1 is a side view of a drug delivery graft according to anembodiment of the present invention;

[0011]FIG. 2 is a side view of a hollow tubing according to anembodiment of the present invention;

[0012]FIG. 3 is a cross-sectional view of the drug delivery graftshowing a cut portion of the hollow tubing according to an embodiment ofthe present invention.

[0013]FIG. 4 is a cross-sectional view of the drug delivery graftshowing a porous hollow tubing according to an embodiment of the presentinvention.

[0014]FIG. 5 is a side view of an alternate embodiment of the drugdelivery graft of the present invention.

[0015]FIG. 6 is a side view of another alternate embodiment of the drugdelivery graft of the present invention.

DETAILED DESCRIPTION OF THE INVENTION

[0016] The following detailed description illustrates the invention byway of example, not by way of limitation, the principles of theinvention. This description will clearly enable one skilled in the artto make and use the invention, and describes several embodiments,adaptations, variations, alternatives and uses of the invention,including what we presently believe is the best mode of carrying out theinvention.

[0017] The present invention satisfies the need for an improved drugdelivery graft capable of delivering bioactive agents, including drugs,to an internal lumen of a graft, either along its entire length or in alocalized area, through the use of hollow tubing on the outside of thegraft. In the detailed description that follows, it should beappreciated that like reference numerals are used to identify likeelements illustrated in one or more of the figures.

[0018] Referring first to FIG. 1, a side view of a drug delivery graft10 in accordance with an embodiment of the present invention isillustrated. The drug delivery graft 10 comprises a graft 2, a hollowtubing 4, and a drug source 6. The hollow tubing 4 is wrapped (spiraled)in a helical fashion around an abluminal surface of the graft 2. Thedrug source 6 is connected to one end 14 of the hollow tubing 4.

[0019] The graft 2 may be a standard clinical vascular graft of anyshape or size comprised preferably of expanded polytetrafluoroethylene(ePTFE), which material consists of a porous network of nodes andfibrils created during the expansion process. This porous networkprovides a somewhat permeable wall for the graft 2. The graft 2 can beconstructed in a variety of sizes to allow a surgeon to select theappropriate size to accommodate a particular vascular application.Likewise, the porosity (internodal distance) of the graft can be variedto affect the rate of drug or agent release.

[0020] The drug delivery graft 10 injects a drug or other agent into thebore of the hollow tubing 4 from the drug source 6. The drug source 6can be any of a variety of commercially and technologically availablesystems that provide constant controlled rate delivery of an agent, suchas a biologically activated mini pump that is either subcutaneously orextracorporeally located, an external mechanical pump, or an accessport. For example, an open end 14 of the hollow tubing 4 may beconnected via a micro-catheter to a subcutaneous or other drug source.

[0021] The agent delivered to the natural tissue conduit can be anysubstance, including any drug, and the device can be used for local orsystemic delivery of such substances to prevent or treat a variety ofdisease syndromes or to promote or enhance desired activity within thebody. A bioactive or diagnostic agent may include, for example,therapeutic or prophylactic agents, such as a drug, protein, enzyme,antibody or other agent, or cells that produce a drug, protein, enzyme,antibody, or other agent. The diagnostic material can include, forexample, a radiolabeled antibody or antigen.

[0022] The natural tissue conduit into which the agent is ultimatelydelivered may include any structure of a body that functions totransport substances and includes, but is not limited to, e.g., bloodvessels of the cardiovascular system (arteries and veins), the lymphaticsystem, the intestinal tract (esophagus, stomach, the small and largeintestines, and colon), the portal system of the liver, the gall bladderand bile duct, the urinary system (bladder, and urethra), therespiratory system (trachea, bronchi and bronchioles), and ducts andductules connecting endocrine organs to other areas of the body. Thedevice of the present invention can be used in any mammal or in anyanimal in which natural tissue conduits are found. Suitable dosagerequirements and treatment regimens for any agent delivered can bedetermined and will vary depending upon the tissue targeted for therapyand upon the particular agent utilized.

[0023] Referring now to FIG. 2, a side view of the hollow tubing 4 usedin an embodiment of the present invention is illustrated. The hollowtubing 4 may be manufactured from a non-expanded or partially expandedsmall diameter PTFE tube or any other implantable polymer (e.g. FEP).The hollow tubing 4 may be manufactured in very small diameters (lessthan 1 mm) and long lengths (more than 10 feet) to accommodate all sizesof grafts. Whereas the prior art beading used solely for supportpurposes is a solid filament, the hollow tubing 4 has a bore to providefluid delivery to the graft 2. Preferably, the hollow tubing 4 has anuncut portion 16 and a partially cut portion 12 (or a porous and less ornon-porous region arrange circumferentially) that allows communicationbetween the lumen of the hollow tubing 4 and the outside surface of thegraft 2. Alternatively, communication between the lumen of the hollowtubing 4 and the outside surface of the graft 2 may be achieved by usinga porous hollow tubing or a hollow tubing with mechanical or laserperforations. While the hollow tubing 4, is shown generally cylindricalin shape, it should be appreciated that alternative designs are possibleincluding a hollow tubing that is tapered along its length as well asone that has a stepped configuration or has other, non-circularcross-sections. Similarly the graft may be tapered or stepped or of aspecial shape, such as cuffed, as is known in the art.

[0024] In a preferred embodiment, to manufacture the hollow tubing 4, aspecified length of a tube made of PTFE, FEP or other any otherimplantable polymer may be loaded on a mandrel to secure the tube in arigid fashion. The loaded tube may be placed in a cutting device where adefined portion of the tube is cut in the longitudinal direction. Asemi-circular “half-tube” C-shaped section 12 may be created in themiddle of the tube to create the hollow tubing 4. The cutting device maycomprise a LASER cutting device. Alternatively, the tube may bepunctured repeatedly or otherwise rendered porous to allow release ofthe agent into the ePTFE of the graft. One end 18 of the hollow tubing 4may be sealed mechanically, for example by a crimp, or by a heatingprocess to terminate the lumen. The terminated end 18 may also be sealedwith a silicon or other self-sealing material that can advantageouslyserve as a primer port for infusing an agent through, for example, asyringe.

[0025] Referring now to FIG. 3, a cross-sectional view of the drugdelivery graft showing a cut portion of hollow tubing according to anembodiment of the present invention is illustrated. Hollow tubing 4 iswound spirally around the graft 2. During the spiraling process, acutaway portion 12 of the hollow tubing 4 is laminated and securedagainst the outer surface of the graft 2, creating a drug outflowsurface that communicates with the outer lumen of the graft 2.Alternatively, FIG. 4 shows a cross-sectional view of the drug deliverygraft showing a porous hollow tubing 24 according to an alternativeembodiment of the present invention. The porous hollow tubing 24comprises perforations or pores 22 through which an agent or drug isdispensed onto and into the graft 2. The agent or drug is evenlydistributed and diffuses into the graft 2 through the interstices of anagent infusion area 8. The rate at which the drug or other agentpenetrates the porous wall of the graft 2 is determined by severalfactors, including the size and number of the pores and the size of thedrug molecule.

[0026] The graft 2 is capable of delivering drugs or any other agents tothe internal lumen along the entire length of the graft 2, or ofrestricting delivery to a finite area on the graft 2. In addition, itshould be appreciated that the spacing of the hollow tubing 4 along thegraft 2 can be varied to concentrate dosages in certain areas of need.Moreover, the spiraling of the hollow tubing 4 around the graft 2, asshown in FIG. 1, could be combined with a traditional support beadingspiraled around the graft 2 for additional support.

[0027] Turning now to FIG. 5, an alternate embodiment of the presentinvention is shown. Drug delivery graft 30 includes graft 32 and hollowtubing 34. In this embodiment, the hollow tubing 34 is arrangedlongitudinally along the graft 32, rather than wrapped around spirallyas in FIG. 1. The hollow tubing 34 is arranged in a snake-like fashion,longitudinally along the outside of the graft 32, and is connected tothe drug source 6 at one end. The longitudinally arranged strips ofhollow tubing 34 loop back at the ends of the graft so that a singlecontinuous piece of hollow tubing is employed. In a second alternateembodiment illustrated in FIG. 6, hollow tubing 44 is arrangedlongitudinally along a graft 42 in a slightly different configuration tomake up a drug delivery graft 40. In this embodiment, the longitudinallyarranged hollow tubing 44 is connected to manifolds 46 and 48 at eachend. The manifold 46, located at a proximal end of the graft 42, iscircumferentially arranged around the graft 42 and is also connected tothe drug source 6. The manifold 48, located at a distal end of the graft42 is circumferentially arranged around the graft 42 in a closed loop.The drug provided from the drug source 6 flows into the manifold 46where it is distributed to the longitudinally placed hollow tubing 44,flowing through the hollow tubing 44 and along the manifold 48, beingdistributed to the graft 42 in one of the above-mentioned methods shownin FIGS. 2-4. It should be appreciated that in both embodiments shown inFIGS. 5 and 6, the hollow tubing can be spaced equidistant or varieddepending on the required application.

[0028] The spiraled or longitudinally-placed hollow tubing is sinteredto the graft to adhere the hollow tubing to the graft in the same manneras existing standard grafts, adhering the cut (C-shaped) portion 12 anduncut hollow tubing portion 16 as shown in FIG. 3, or the porous hollowtubing 24 as shown in FIG. 4, along the length of the graft 2.Alternatively, any of a number of known adhesive agents can be used toattach the hollow tubing. Further, the hollow tubing may be producedfrom a plastic material such as polypropylene, which can be adhered tothe graft through a partial melting process. Thus, the design may usethe existing low profile hollow tubing on existing grafts, for exampleIMPRAFlex® grafts, manufactured by IMPRA (Tempe, Ariz.), a Division ofC. R. Bard, Inc., and can be implanted in the same fashion as regularlyused existing vascular grafts.

[0029] The devices of the present invention can function as improvedvascular grafts such that the agent or drug to be delivered prevents ortreats complications associated with conventional vascular graftplacement, including but not limited to platelet deposition,coagulation, thrombosis, neointimal hyperplasia and fibrosis. Oneparticularly attractive use of the drug delivery graft would be todispense drugs or any other agent to limit the stenosis that frequentlyoccurs at the site of anastimosis of an ePTFE graft to a blood vessel.Examples of agents that prevent restenosis of a blood vessel include,but are not limited to, a growth factor, a growth factor inhibitor,growth factor receptor antagonist, transcriptional repressor,translational repressor, antisense DNA, antisense RNA, replicationinhibitor, anti-microtubule agents, inhibitory antibodies, antibodiesdirected against growth factors or their receptors, bifunctionalmolecules comprising a growth factor and a cytotoxin, and bifunctionalmolecules comprising an antibody and a cytotoxin.

[0030] The present invention has been described above in terms of apresently preferred embodiment so that an understanding of the presentinvention can be conveyed. However, there are many alternativearrangements for an expanded PTFE drug delivery graft not specificallydescribed herein but with which the present invention is applicable. Thescope of the present invention should therefore not be limited by theembodiments illustrated, but rather it should be understood that thepresent invention has wide applicability with respect to drug deliverygrafts generally. All modifications, variations, or equivalent elementsand implementations that are within the scope of the appended claimsshould therefore be considered within the scope of the invention.

We claim:
 1. A drug delivery graft, comprising: a graft comprising alumen defined by an outer wall, wherein the outer wall is characterizedby a microstructure having nodes interconnected by fibrils; and drugdelivery means coupled to the outer wall for delivering a drug thereto,wherein the drug diffuses into the lumen through the outer wall.
 2. Thedrug delivery graft according to claim 1, further comprising a drugsource coupled to the drug delivery means.
 3. The drug delivery graftaccording to claim 1, wherein the drug delivery means comprises a hollowtube.
 4. The drug delivery graft according to claim 3, wherein thehollow tube is arranged substantially parallel to a longitudinal axis ofthe graft.
 5. The drug delivery graft according to claim 3, wherein thehollow tube comprises a cutaway portion in communication with the outerwall.
 6. The drug delivery graft according to claim 3, wherein thehollow tube comprises perforations in communication with the outer wall.7. The drug delivery graft according to claim 3, wherein the hollow tubecomprises a porous wall in communication with the outer wall.
 8. Thedrug delivery graft according to claim 1, wherein the graft comprisesexpanded polytetrafluoroethylene.
 9. The drug delivery graft accordingto claim 1, wherein the drug is selected from the group consisting of agrowth factor, a growth factor inhibitor, growth factor receptorantagonist, a transcriptional repressor, a translational repressor, anantisense nucleic acid, a replication inhibitor, an anti-microtubuleagent, an inhibitory antibody, an antibody directed against a growthfactor, a bifunctional molecules comprising a growth factor and acytotoxin, and a bifunctional molecule comprising an antibody and acytotoxin.